中村 肇伸
(なかむら・としのぶ)
Toshinobu Nakamura
略歴
- 大阪大学大学院薬学研究科生命情報環境科学専攻博士後期課程修了
- 大阪大学微生物病研究所遺伝子動態研究分野研究員、大阪大学大学院生命機能研究科時空生物学病因解析学特任研究員、大阪大学大学院医学系研究科幹細胞病理学助教を経て本学へ
エピジェネティック制御学研究室
卒業研究テーマ例
- 全能性細胞の可視化と全能性幹細胞の樹立
- 全能性細胞で特異的に発現するTrim61の機能解析
- 全能性細胞特異的遺伝子を用いた高品質iPS細胞の作製
受精後の全能性再獲得の分子機構
全能性細胞の可視化とその誘導
受精卵におけるエピジェネティックリプログラミング機構
- 研究の応用領域
- 医薬品・診断薬の開発、再生医療分野の新技術開発
- 産官学連携で求めるパートナー
- 幹細胞、再生医療、生殖医療分野の基礎・応用・臨床研究者医薬品・診断薬開発、再生医療、生殖医療の関連企業、大学、国・地方自治体の研究機関
During mammalian development, different cells and tissues acquire different programs of gene expression. Epigenetic regulations such as DNA methylation and histone tail modification play pivotal roles in this process, as well as transcriptional and translational regulation. A decade after cloning Dolly the sheep, the induction of pluripotency by transcription factors has been reported and brought about prospects for regenerative medicine. However, the establishment of topipotency during natural reproduction is exceedingly more efficient than in reproductive cloning or in transcription factor-based reprogramming. Understanding the molecular mechanisms directing acquisition of totipotency during early embryogenesis may enable to optimize the protocols for inducing reprogramming. We are investigating the mechanisms of epigenetic reprogramming occur after fertilization and during nuclear reprogramming
Molecular mechanisms underlying totipotency.
Although the sperm and oocyte are highly specified cells to pass genetic information to next generation, they acquire totipotency, the ability to differentiate into any type of cell in the body, soon after fertilization. We have identified the genes specifically expressed in totipotent cells (totipotent-cell specific genes) in silico. We are investigating whether these genes are required for acquisition and/or maintenance of totioptency by gene disruption study in mice.
Visualization and induction of totipotent cells within the ES cell clture.
Embryonic stem (ES) cells were thought to pluripotent cells, which lack the ability to make all extra-embryonic tissues. However, a recent study revealed that a rare fraction of ES cells culture, that expresses high levels of murine endogenous retrovirus with leucine tRNA primer (MuERV-L), have totipotency. We have identified totipotent cells in ES cell culture by visualizing the expression of MuERV-L, and found the culture condition which can efficiently induce totipotency . We are trying to generate “totipotent stem cells” which can differentiate to both embryonic and extraembryonic lineages using totipotent-cell specific genes.
Epigenetic reprogramming in fertilized egg.
After fertilization, paternal genome undergoes epigenetic reprogramming, whereas the maternal genome appears epigenetically more static. We found that 5-methylcytosine (5-MeC) was converted to 5-hydroxymethylcytosine (5-HmC) in paternal genome after fertilization. Furthermore, we found that PGC7 (also known as Stella and Dppa3) protects the maternal genome from the conversion of 5MeC to 5-HmC. Recently, we found that novel histone modification is present in the paternal chromatin. We are investigating whether this modification is required for epigenetic reprogramming in zygote.
Hatanaka Y, Tsusaka T, Shimizu N, Morita K, Suzuki T, Machida S, Satoh M, Honda A, Hirose M, Kamimura S, Ogonuki N, Nakamura T, Inoue K, Hosoi Y, Dohmae N, Nakano T, Kurumizaka H, Matsumoto K, Shinkai Y, Ogura A., Histone H3 methylated at arginine 17 is essential for reprogramming the paternal genome in zygotes. Cell Rep, 20, 2756-2765 (2017)
Xu X*, Smorag L*, Nakamura T*, Kimura T, Dressel R, Fitzner A, Tan X, Linke M, Zechner U, Engel W , Pantakani K. (*co-f irst authors), Dppa3 expression is critical for generation of fully-reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting. Nat Commun., 6, 6008 (2015)
Nakamura T, Liu YJ, Nakashima H, Umehara H, Inoue K, Matoba S, Tachibana M, Ogura A, Shinkai Y, Nakano T., PGC7 binds histone H3K9me2 to protect against conversion of 5MeC to 5HmC in early embryos. Nature, 486, 7403, 415-419 (2012)
Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J., 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun., 2, 241 (2011)
Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H, Sekimoto T, Ikawa M, Yoneda Y, Okabe M, Tanaka T, Shiota K, Nakano T., PGC7/ Stella protects against DNA demethylation in early embryogenesis, Nature Cell Biol.,9, 1, 64-71 (2007)